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Clonal associations between lymphocyte subsets and functional states in rheumatoid arthritis synovium

2024; Nature Portfolio; Volume: 15; Issue: 1 Linguagem: Inglês

10.1038/s41467-024-49186-0

2041-1723

Garrett S. Dunlap, Aaron B. Wagner, Nida Meednu, Ruoqiao Huiyi Wang, Fan Zhang, Jabea Cyril Ekabe, A. Helena Jonsson, Kevin Wei, Saori Sakaue, Aparna Nathan, Jennifer S. Albrecht, William Apruzzese, Jennifer L. Barnas, Joan M. Bathon, Ami Ben‐Artzi, Brendan F. Boyce, S. Louis Bridges, Debbie Campbell, Hayley L. Carr, Arnold Ceponis, Adam Chicoine, Andrew Cordle, Michelle Curtis, Kevin D. Deane, Edward F. DiCarlo, Patrick Dunn, Lindsy Forbess, Laura Geraldino‐Pardilla, Ellen M. Gravallese, Peter K. Gregersen, Joel M. Guthridge, Diane Horowitz, Laura B. Hughes, Kazuyoshi Ishigaki, Lionel B. Ivashkiv, Judith A. James, Joyce B. Kang, Gregory Keras, Ilya Korsunsky, Amit Lakhanpal, Eddie A. James, Yuhong Li, Zhihan J. Li, Katherine P. Liao, Holden Maecker, Arthur M. Mandelin, Ian Mantel, Mark Maybury, Mandy J. McGeachy, Joseph Mears, Alessandra Nerviani, Dana E. Orange, Harris Perlman, Javier Rangel‐Moreno, Karim Raza, Yakir Reshef, Christopher T. Ritchlin, Felice Rivellese, William H. Robinson, Laurie Rumker, Ilfita Sahbudin, Karen Salomon-Escoto, Dagmar Scheel‐Toellner, Jennifer Seifert, Anvita Singaraju, Melanie H. Smith, Paul J. Utz, Kathryn Weinand, Dana Weisenfeld, Michael H. Weisman, Qian Xiao, Zhu Zhu, Vivian P. Bykerk, Laura T. Donlin, Susan M. Goodman, Gary S. Firestein, David L. Boyle, V. Michael Holers, Larry W. Moreland, Darren Tabechian, Costantino Pitzalis, Andrew Filer, Soumya Raychaudhuri, Michael B. Brenner, Juilee Thakar, Andrew McDavid, Deepak A. Rao, Jennifer H. Anolik,

Cytokine Signaling Pathways and Interactions

Abstract Rheumatoid arthritis (RA) is an autoimmune disease involving antigen-specific T and B cells. Here, we perform single-cell RNA and repertoire sequencing on paired synovial tissue and blood samples from 12 seropositive RA patients. We identify clonally expanded CD4 + T cells, including CCL5+ cells and T peripheral helper (Tph) cells, which show a prominent transcriptomic signature of recent activation and effector function. CD8 + T cells show higher oligoclonality than CD4 + T cells, with the largest synovial clones enriched in GZMK+ cells. CD8 + T cells with possibly virus-reactive TCRs are distributed across transcriptomic clusters. In the B cell compartment, NR4A1+ activated B cells, and plasma cells are enriched in the synovium and demonstrate substantial clonal expansion. We identify synovial plasma cells that share BCRs with synovial ABC, memory, and activated B cells. Receptor-ligand analysis predicted IFNG and TNFRSF members as mediators of synovial Tph-B cell interactions. Together, these results reveal clonal relationships between functionally distinct lymphocyte populations that infiltrate the synovium of patients with RA.